Apolipoprotein A‐IV acts as an endogenous anti‐inflammatory protein and is reduced in treatment‐naïve allergic patients and allergen‐challenged mice

BACKGROUND: Recent studies pointed to a crucial role for apolipoproteins in the pathogenesis of inflammatory diseases. However, the role of apolipoprotein‐IV (ApoA‐IV) in allergic inflammation has not been addressed thoroughly thus far. OBJECTIVE: Here, we explored the anti‐inflammatory effects and underlying signaling pathways of ApoA‐IV on eosinophil effector function in vitro and in vivo. METHODS: Migratory responsiveness, Ca(2+)‐flux and apoptosis of human peripheral blood eosinophils were assessed in vitro. Allergen‐driven airway inflammation was assessed in a mouse model of acute house dust mite‐induced asthma. ApoA‐IV serum levels were determined by ELISA. RESULTS: Recombinant ApoA‐IV potently inhibited eosinophil responsiveness in vitro as measured by Ca(2+)‐flux, shape change, integrin (CD11b) expression, and chemotaxis. The underlying molecular mechanism involved the activation of Rev‐ErbA‐α and induced a PI3K/PDK1/PKA‐dependent signaling cascade. Systemic application of ApoA‐IV prevented airway hyperresponsiveness (AHR) and airway eosinophilia in mice following allergen challenge. ApoA‐IV levels were decreased in serum from allergic patients compared to healthy controls. CONCLUSION: Our data suggest that ApoA‐IV is an endogenous anti‐inflammatory protein that potently suppresses effector cell functions in eosinophils. Thus, exogenously applied ApoA‐IV may represent a novel pharmacological approach for the treatment of allergic inflammation and other eosinophil‐driven disorders.